Vitamin D

Introduction

• Fat-soluble vitamin

• 40% of adults >20 years had Vit D levels below 50 nmol/L

Chemistry

• The major circulatory form is 25-hydroxyvitamin D

• Half-life is 2 to 3 weeks

• The active form is 1,25-dihydroxy vitamin D

• This is 100x more potent and half-life is 4 to 6 hours

• Promotes calcium absorption from gut, phosphate absorption from intestine, suppresses PTH, regulates osteoblasts

Sources

• Very few foods contain vitamin D (except fatty fish livers)

• Dermal synthesis is the main source

• Brief casual sun exposure on the arms and face is equivalent to 200 IU ingested

• But this varies due to skin type, latitude, season and time of day

• Infants, disabled persons and older adults may have inadequate sun exposure

• Older adults do not covert vitamin D as well

• At northern latitudes, not enough radiation to convert vitamin D, particularly in Winter

• Some foods are fortified including infant formula, breakfast cereals

Absorption

• Dietary vitamin D is put in micelles

• Absorbed by enterocytes

• Packed into chylomicrons

• Disorders linked with fat malabsorption such as coeliac are linked with low vitamin D

Metabolism

• Vitamin D from diet or dermal synthesis is biologically inactive and requires enzymatic conversion in the liver and kidney to active metabolites

• Increased PTH and hypophosphatemia enhance Vitamin D production.

• Vitamin D in turn inhibits PTH.

Requirements

• RDI is 600IU up until 70 years

• RDI is 800 IU after 70 years

• Infants under 12 months only need 400 IU

• These are based on effects on skeletal health only

Levels

• Serum levels of 50nmol/L are sufficient for most people

Deficiency or resistance

• Impaired availability of Vit D due to inadequate intake, malabsorption and/or lack of sunlight

• Impaired hydroxylation by the liver

• Impaired hydroxylation by the kidneys

• End organ insensitivity to Vitamin D e.g. hereditary rickets

Excess

• Uncertain at what point intake becomes toxic

• Tolerable upper intake level at 4000IU daily for

  • Healthy adults

  • Kids 9 to 18

  • Pregnant and lactating women

• Those with malabsorption may need a daily dose of 10,000 to 50,0000 to replete levels whilst being carefully monitored

• Vitamin D intoxication has been documented in adults taking 60,000IU daily

• Prolonged skin exposure does not cause intoxication

Intoxication symptoms

• Hypercalcaemia

• Increased confusion

• Polyuria

• Polydipsia

• Anorexia

• Vomiting

• Muscle weakness

Vitamin D Deficiency

Causes

• Decreased intake or absorption

• Reduced sun exposure

• Increased hepatic catabolism

• Decreased synthesis

Groups at high risk

• Older people who are confined indoors

• Northern latitude

• Those taking medications that accelerate Vit D metabolism e.g. phenyotoin

• Hospitalised

• Institutionalised

• Increased skin pigmentation

• Obesity

• Limited sun exposure

• Osteoporosis

• Malabsorption

Who to test?

• Those in the high-risk groups above

Clinical manifestations

• Mild or moderate levels are usually asymptomatic

• PTH is elevated in as many as 40 % of patients with Vit D <50nmol/L and 50% of those less than 25nmol/L

• Those with low vitamin D and secondary elevations in PTH are at increased risk of accelerated bone loss

• With severe vitamin D deficiency, there is reduced absorption of CMP, causing elevated PTH, leading to the demineralisation of bones

• Can lead to osteomalacia and rickets

• Associated symptoms of bone tenderness, muscle weakness, fracture and difficulty walking

Evaluation

• If vitamin D < 30 then measure CMP, AP, UEC, Coeliac

• Some argue measuring above tests at levels <50

• XRAY only if bone pain

• Don’t do BMD if the only issue is low Vitamin D

Replacement

• Use cholecalciferol (Vit D 3)

• The dose depends on the absorptive capacity

• In those with normal absorption, 100IU increases the level by 2nmol/L

• If less than 30nmol/L, consider 50,000IU weekly for 8 weeks, and then 800IU daily ongoing (seems aggressive)

• For those 30 to 50nmol/L give 800-1000IU daily for 3 months and recheck the level.

• If 50-75nmol/L then 600-800IU daily is enough

• For patients with malabsorption, doses of 10,000 to 50,000IU may be needed short term whilst monitored

Safety

• One trial showed a large annual oral dose of 500,000IU had an undesired effect on increasing falls and fractures in older adults

• Monthly dosing of 60,000 and 100,000IU had the undesirable effect of increasing falls in older adults

Pregnancy

• The optimal level is not known, should be at least 50nmol/L

• RDI is 600IU, most prenatal vitamins contain 400IU

• One trial shows doses of 400, 2000 and 4000IU daily is safe

CKD

• Patients with eGFR > 30 should have similar vitamin D supplementation as normal people

• As eGFR <30, calcitriol production may be low and vitamin D supplementation in this group is needed

Malabsorption

• Higher doses needed

• Patients who remain deficient might need calcitriol with sun or sunlamp exposure

Primary hyperparathyroidism

• Some patients have vitamin D deficiency AND primary hyperPTH

• Hypercalcaemia may not be evident if the vitamin D deficiency is severe

• Vitamin D replacement here should be done cautiously

Monitoring

• Healthy adults on Vitamin D supplementation do not require an initial or follow-up measurement

• Those being treated for Vit D < 50nmol/L can have a repeat test in 3-4 months to check dose is sufficient

Benefits of treatment

• Skeletal

  • Osteoporosis

• Prevention of falls

  • Improved muscle function

• Extraskeletal benefits

Extraskeletal Benefits

• Large number of epidemiologic data showing the risks of cancer, infections, autoimmune and cardiovascular diseases are higher when vitamin D levels are <50nmol/L

• Risk decreases with higher concentrations

• No convincing RCT that vitamin D supplement can decrease any of those diseases

• No prospective studies looking at optimal vitamin D level for extraskeletal health

• No suggestion to give vitamin D above and beyond what is needed for osteoporosis management

COVID19

• Trial showed no improvement in COVID severity between of 800IU versus 3200IU daily

Muscle function

• Observational studies suggest an association between poor vitamin D status and muscle weakness in children and older individuals

• No causal relationship between vitamin D supplementation and improvement in muscle weakness clearly demonstrated in RCT

Falls

• Vitamin D supplementation in community-dwelling adults does not reduce the risk of falls

Colon cancer

• WHO working group found an association between low Vit D and the risk of colon cancer

• Supported by data from 17 cohorts

• Vitamin D levels <30 have increased risk compared to those >50

• RR = 1.31

Breast cancer

• Observational studies inconsistent

• Meta-analysis of prospective studies showed risk of breast cancer in post-menopausal women decreased with Vit D between 67 and 87nmol/L.

• No further decreases above 87nmo/L

Prostate Cancer

• No consistent relationship

Cancer prevention

• Most trials show no reduction in cancer risk with Vitamin D supplementation

Cancer treatment

• Current evidence is insufficient to support large-dose vitamin D supplementation to treat cancer

Immune system

• The causal link remains unclear

• Vitamin D has effects on all cells of the immune system

• Antigen-presenting cells express vitamin D receptors (VDR)

• Vitamin D -VDR system can modulate most aspects of the acquired and innate immune system

• Vitamin D reduces activation of the acquired immune system but actives the innate system

Autoimmunity

• Active Vitamin D inhibits dendritic cell maturation and works as an immune modulator

• Observational studies suggest an association between vitamin D deficiency and T1DM, MS, and IBD

• VITAL trial, 25k participants given 2000IU or placebo, followed 6 years, the cumulative incidence of autoimmune disease was lower in the treatment group (0.9% versus 1.2%)

Multiple Sclerosis

• 7 million US military personnel, vitamin D levels below 50nmol/L had a 2 fold increased risk for MS

Asthma

• Unclear

• One trial showed no link with Vit D Supp and improvement in corticosteroid responsiveness

• One trial showed no link in time to severe asthma exacerbation

• One trial showed Vit D supp in asthma had a significantly bettwer FEV1

• One trial in prem infants showed Vit D reduced risk of recurrent wheezing by 12 months

• Lower rate of persistent wheezing in infants to mothers given Vit D at 2800IU

• Lower rates of asthma / wheezing in infants to mother’s given Vit D 4400IU versus 400IU from 10/40 to 18/40 - no difference at 6 years of age

Infection

• No causal relationship between Vitamin D and infection established

Tuberculosis

• Association between vitamin D deficiency and TB

• There is a beneficial effect of ultraviolet B exposure before antibiotics therapy was available

• Vitamin D supplementation does not improve clinical outcomes in patients with TB

• Small study showed vitamin D supplementation accelerated sputum clearance in patients with TB

• Vitamin D supp did not prevent latent or active TB in vit-D deficient kids in Mongolia

URTI

• Not enough evidence to support high-dose vit D for the prevention of URTIs

• Meta-analysis of trials suggested a small reduction in the occurrence of URTIs with vit D supp

• Subsequent trials have not reported a benefit

COPD exacerbations

• Insufficient evidence to support use to prevent acute COPD exacerbations

• Meta-analysis showed vit D supp did not change overall rate of moderate to severe COPD

• There was a protective effect in patients with a baseline serum Vit D < 25 nmol/L given Vit D

Cardiovascular System

• Observational studies show a link between low vitamin D and risk of hypertension and cardiovascular events

• Most randomised trials have not shown a benefit of vit D supplementation

• Causal nature remains uncertain

Hypertension

• No benefit of vit D supp

Cardiovascular events

• No benefit of vit D supp

• Framingham Offspring Study, patients who had vit D <37.5nmol/L were more likely to have their first cardiovascular event than those with a vit D >37.5nmol/L

• NHANES study showed IHD is more common if vit D < 50 compared to >75

• Also rate of heart failure and PVD was higher if vit D < 50

Diabetes

• Some but not all observational studies suggest an association between low vit D and T1DM

• Link between T1DM and key genetic polymorphisms linked to vit d deficiency

• Several observational studies, mostly case-controlled, showed vit D supp in early infancy reduced the subsequent risk of T1DM by 30%

• Vit D levels are lower in people with obesity and T2DM

Glycaemia

• Vit d supp imparts negligible or no improvement in glycaemia

• May confer some metabolic improvement with individuals with overt vit D deficiency

Neuropsychiatric Function

• Lower levels of vitamin D frequent in patients with depression and Alzheimer’s disease

• Meta-analysis shows MMSE scores in patients with lower serum vit D <50 versus >50

• Meta-analysis showed no significant effect of vit D supp on depression symptoms but low-quality studies

Pregnancy Outcomes

• Poor vitamin D status in the perinatal period may have short-term (pre-eclampsia) or long-term consequences (in the offspring) on bone, immune system and general health.

• Threshold for optimal vit D status is not well defined

• Observational studies show association between poor maternal vit D status and adverse pregnancy

• Low vit D associated with higher risk of GDM, pre-eclampsia and small for gestational age infants

• Two studies showed reduced risk of low birth weight infants but not preterm birth

• 2018 meta-analysis compared vit D supp versus placebo, supp reduced the risk of small for gestation age.

• The effect on fetal or neonatal mortality (1.8 vs 2.2) was not significant

Mortality

• Large-scale epidemiological data show an association between low vit D and higher mortality risk

• Some meta-analyses show modest reduction in all-cause mortality with vit D supp (particularly older, non-critically ill vit D- deficient patients)

• Subsequent trials in critically ill adults or adults without vid D deficiency showed no reduction in mortality

• Study of genetic polymorphisms showed association with low vit D and all-cause mortality

• No benefit of monthly 60,000 IU on 20k Australians followed 6 years in terms of overall mortality

Cardiovascular mortality

• No significant difference between 2000IU versus placebo followed for 6 years in terms of cardiovascular mortality

Cancer mortality

• NHANES data = no association between vit D levels and overall cancer mortality